Beruflich Dokumente
Kultur Dokumente
doi:10.1093/eurjhf/hfs070
Department of Cardiology, Haydarpasa Numune Education and Research Hospital, Turkey; 2Department of Cardiology, Siyami Ersek Cardiovascular Surgery Center, Turkey;
Department of Obstetrics and Gynecology, Ortaca Yucelen Hospital, Turkey; and 4Section of Cardiology, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical
Center, and Winters Center For Heart Failure Research, Baylor College of Medicine, Houston, TX, USA
3
Received 21 February 2012; revised 26 March 2012; accepted 12 April 2012; online publish-ahead-of-print 15 May 2012
Aims
Persistence of left ventricular (LV) systolic dysfunction after 6 months of diagnosis is believed to be a marker of an
irreversible cardiomyopathy in peripartum cardiomyopathy (PPCM). We sought to determine the length of time
required for recovery of LV systolic function (LVSF) in patients with PPCM.
.....................................................................................................................................................................................
Methods
Forty-two consecutive women with PPCM were enrolled in this prospective study. The minimum required time of
and results
follow-up for inclusion was 30 months. Each patient underwent transthoracic echocardiography, and plasma brain
natriuretic peptide (BNP) and C-reactive protein measurement at admission, and every 3 months. Early recovery
was defined as normalization of LVSF at 6 months post-diagnosis. Delayed recovery was defined if the length of
time required for recovery of LVSF was longer than 6 months. Persistent left ventricular dysfunction (PLVD) was
defined as an ejection fraction of ,50% at the end of follow-up. Twenty patients (47.6%) recovered completely,
10 died (23.8%), and 12 (28.6%) had PLVD. Average time to complete recovery was 19.3 months after initial diagnosis
(3 42 months). Early recovery was observed only in six patients (30%), whereas delayed recovery was observed in
14 out of 20 patients (70%). Patients with complete recovery were more likely to have a higher LV ejection fraction
and smaller LV end-systolic dimensions at baseline.
.....................................................................................................................................................................................
Conclusion
Full recovery of LVSF in PPCM patients often requires longer than 6 months.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Introduction
Peripartum cardiomyopathy (PPCM) is an idiopathic or familial cardiomyopathy presenting with heart failure secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the
months following delivery, where no other cause of heart failure is
found.1,2 Though no specific treatment strategies exist for PPCM,
current therapeutic options consist of conventional supportive
therapy for heart failure and it is similar to that of other forms of
congestive heart failure in pregnancy.2 4 This includes mainly
symptom control, aiming at reduction in afterload and preload, augmentation of myocardial contractility, and anticoagulation therapy. In
spite of the recent advances in the management of PPCM including
bromocriptine therapy,5 the course and outcome are usually unpredictable. Previous reports showed that most of the women with
Methods
Patients
The inclusion criteria included: (i) symptoms of congestive heart failure
that developed towards the end of pregnancy or in the first 5 months
post-partum; (ii) no other identifiable cause of heart failure; (iii)
* Corresponding author. Bankalar Caddesi, Horoz Apt, 4/7 Cevizli/Kartal, Istanbul, Turkey. Tel: +90216 4144502, Fax: +902163360565, Email: murbit2@yahoo.com
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com.
896
absence of recognizable heart disease before the last month of pregnancy; and (iv) left ventricular ejection fraction (LVEF) ,45% by transthoracic echocardiography. Patients with a history of significant
hypertension or valvular heart disease were excluded. We enrolled
49 patients that matched the inclusion criteria. However, five patients
were excluded from the study because they were lost to follow-up and
two patients were excluded because they were determined to be noncompliant with their therapeutic regimens. Forty-two consecutive
women with newly diagnosed PPCM admitted to two tertiary hospitals
in Istanbul, Siyami Ersek Cardiovascular Surgery Center and Kosuyolu
Kartal Heart Education and Research Hospital, between February 2005
and January 2009, who met the inclusion criteria were included in the
study. All patients in the study were diagnosed with PPCM for the first
time. Clinical evaluation including history, physical examination, and assessment of LVSF by transthoracic echocardiogram was performed at
the time of admission, then every 3 months during the first year, every
6 months thereafter, and whenever clinically indicated. Complete
blood count, routine biochemical analyses, and brain natriuretic
peptide (BNP) and C-reactive protein concentrations were also
determined.
Mean follow-up period was 38.9 + 14.7 months (range 4 65
months) including the patients who died. For the subgroup of 36
patients who survived beyond 12 months, the mean follow-up was
44.0 + 8.1 months (range 30 65 months) after the diagnosis of
PPCM. Written informed consent was obtained from each patient
before entry into the study and the protocol was approved by the Institutional Review Boards.
Therapy
All patients were treated with diuretics (furosemide), beta-blockers, and
angiotensin-converting enzyme inhibitors. The angiotensin-converting
enzyme inhibitor of choice was captopril (6.25 mg initial dose titrated
up to 50 mg twice daily) which was used only in patients who were
post-partum due to known teratogenic effects. The beta-blocker
carvedilol was initiated after stabilization of decompensated heart
failure, and the dose was slowly up-titrated to a target of 25 mg
twice daily as tolerated. Patients with an EF 25% or LV thrombus
received anticoagulation therapy for 6 months. Furosemide dose was
adjusted as indicated according to clinical assessment during the
study period. Fifteen patients also received digoxin therapy. Six
patients required inotropic support, and two required an intra-aortic
balloon pump at the time of referral.
Echocardiography
Standard transthoracic echocardiography was performed in all patients
at baseline, then every 3 months during the first year and every
6 months thereafter for the duration of follow-up using the Vivid
Three System (Vivid 3 pro, GE Vingmed, Milwaukee, WI, USA). Baseline LVEF was measured by transthoracic echocardiography using the
M. Biteker et al.
Statistical analysis
Data were analysed using SPSS for Windows (version 15, SPSS Inc.,
Chicago, IL. USA). The continuous variables were expressed as
mean + standard deviation and were compared between groups by
two-tailed Student t-test. Non-parametric tests were also used when
necessary (Mann Whitney U-test). Fishers exact (x2) test was used
in comparison of categorical variables. Statistical differences among
groups were tested by one-way analysis of variance (ANOVA) and
Kruskal Wallis tests for parametric and non-parametric variables, respectively. Univariate and multivariate logistic regression analyses were
conducted to identify variables predictive of recovery and death. Variables related to the hazard (risk) of an event were assessed using stepwise multivariable Cox proportional hazards models. For all analyses,
P , 0.05 was considered statistically significant.
Results
Patients
The mean age of the patients was 27.0 + 5.2 years (range 18 35),
and the number of parities ranged from one to four. Two patients
(4.8%) had twin pregnancies and seven patients (16.7%) had gestational hypertension. Twelve patients (28.6%) were diagnosed
during the pre-partum period and 30 (71.4%) were diagnosed
post-partum (Table 1).
Clinical outcomes
Ten patients (23.8%) died between the sixth day of delivery and
5 years post-partum. Five of the deaths were due to progression
of heart failure and the others were due to sudden death.
All patients who suffered from sudden cardiac death had an EF
of , 40% at their last visit. Of the remaining 32 survivors, 20 completely recovered (6 early recovery and 14 delayed recovery) and
12 were left with PLVD (Figure 1). The shortest time from diagnosis to recovery was 3 months and the longest time was 42 months.
The LVEF values at the initial examination and at the last follow-up
are shown in Figure 2. In the present study, the time to recovery of
LVSF was . 1 year in 60% of the patients. Four patients (2 patients
with complete recovery and 2 patients with partial recovery)
showed delayed deterioration (12, 24, 26, and 34 months after
diagnosis) during the study period. Of the four patients with spontaneous deterioration of LVSF, two patients with partial recovery
were receiving full-dosage heart failure treatment, but two patients
with complete recovery stopped taking their medications after recovery and had delayed deterioration at 24 and 34 months.
Predictors of mortality
In the population studied, mortality was high (23.8%). Significant
differences were noted in the baseline characteristics between
deceased patients and survivors; including LV end-systolic diameter
(6.3 + 0.8 cm vs. 5.6 + 0.6 cm, respectively, P 0.008) and LVEF
(19.7 + 5.6% vs. 27.6 + 5.6%, respectively, P ,0.001) (Table 2).
897
27.0 + 5.2
2.5 + 1.0
Follow-up (months)
38.9 + 14.7
Follow-up (months)a
Onset of symptom (n, %)
44.0 + 8.1
Pre-partum
Post-partum
NYHA (n, %)
12 (28.6)
30 (71.4)
II
7 (16.7)
III
IV
13 (31.0)
22 (52.4)
5 (11.9)
Hypertension (n, %)
Diabetes mellitus (n, %)
7 (16.7)
2 (4.8)
Echocardiography
LVESD (cm)
LVEDD (cm)
5.7 + 0.7
6.6 + 0.6
LVEF (%)
25.7 + 6.5
PASP (mmHg)
Left ventricular thrombus
44.4 + 12.8
4 (9.5)
Medication (n, %)
Digoxin
ACE inhibitor
15 (35.7)
34 (81.0)
Diuretic
42 (100.0)
Beta-blocker
Intra-aortic balloon pump
38 (90.5)
2 (4.8)
CRP (mg/dL)
5.2 + 3.2
BNP (pg/mL)
623.9 + 328.1
Figure 1 Outcome in 42 patients with peripartum cardiomyopathy. PLVD, persistent left ventricular dysfunction.
Predictors of recovery
There were no significant differences in age, degree of parity,
NYHA functional capacity, medication, pulmonary artery systolic
pressure, LV end-diastolic diameter, or presence of LV thrombi
between patients who recovered completely and those who did
not recover (Table 3). Initial LV end-systolic diameter (5.4 + 0.5
cm vs. 6.1 + 0.7 cm, P 0.003, respectively) was significantly
lower, and initial LVEF (29.7 + 4.3% vs. 22.1 + 6.1%, P 0.001,
respectively) values were significantly higher in patients with complete recovery (early + delayed recovery) compared with the
patients who did not recover. On multivariate logistic regression
analysis, only baseline LVEF (adjusted OR 1.193, 95% CI 0.993
1.433; P , 0.05) remained as a significant variable associated with
recovery. Baseline BNP and C-reactive protein values were
similar in patients with early recovery, delayed recovery, and
non-recovery (Table 3).
Discussion
The major finding of our study is that although 30% of patients
diagnosed in Turkey who recover do so within the first 6 months
post-partum, there is a significant proportion of patients with
PPCM who continue to recover beyond 6 months. Indeed in our
study, among the patients who recovered, 60% achieved recovery
beyond a year. The second important finding is that there is a
subgroup of patients who may develop late deterioration after
12 months in LV function after an initial recovery. Finally, we
demonstrated that advanced remodelling and low LVEF were predictors of mortality and non-recovery.
Previous studies have reported that LVSF recovery usually
occurs within 6 months of diagnosis in many of the patients, and
if the heart failure persists after 6 months it is probably irreversible
and associated with a worse survival in PPCM.2,3 Elkayam et al.
evaluated 40 patients with longitudinal follow-up of 30 + 29
months and showed that improvement usually occurred within
the first 6 months after the diagnosis.6 However, two recent
studies have demonstrated late recovery in patients with
PPCM.7,9 In the first study, Fett et al. evaluated 116 PPCM patients
(mean follow-up time was 35 months) and detected slow responders.7 Despite the lower recovery rate of Haitian PPCM patients
(28%) possibly related to the lack of consistent use of betablockade prior to 2008 due to economic factors, 17 out of the
32 patients (53.1%) recovered over 18 months (range 348
months). In the second study, Modi et al. retrospectively evaluated
44 patients with PPCM in the USA.9 Although the majority of the
898
M. Biteker et al.
Figure 2 Left ventricular ejection fraction at the initial examination and at the last follow-up in patients with delayed recovery (A), early recovery (B), persistent left ventricular dysfunction (C), and mortality (D).
patients were African American and indigent, the 9-year nonrecovery rate was 30% and median time to recovery was
54 months.
In our study over an average follow-up period of 38.9 months,
the overall non-recovery rate of our Turkish metropolitan cohort
was 52%, with a mortality rate of 23.8% despite a high prevalence
of use of beta-blockers (91%) and angiotensin-converting enzyme
inhibitors (81%). The non-recovery rates in our cohort are lower
than in the Haitian cohort described by Fett et al.7 but higher than
the US cohorts described by Modi et al. (mortality rate 15.9%)9
or others (mortality rates 05%).10 We have recently reported
30% and 25% mortality in Turkish women with PPCM.11,12 In the
present study almost half of the patients recovered completely
(47.6%), but the mortality rate was still high (23.8%).
This can potentially be explained by higher angiotensin-converting
enzyme inhibitor and beta-blocker use than the Haitian patients, but
lower use of bromocriptine, devices (implantable cardioverter defibrillator, cardiac resynchronization therapy), or advanced heart failure
therapies such as ventricular assist device support or cardiac transplantation than the US patients. Importantly, however, similar to the
above studies, we demonstrated that there are late responders
who recover beyond 6 or even 12 months on background
medical therapy, and full recovery of LVSF in PPCM patients
often occurs after the first 6 months following diagnosis. The implications of these findings is that though early recovery may be a
good prognosticator, lack of recovery by 6 months should not
rule out potential late recovery. These results also implicate that
recovery from PPCM can be very prolonged ( . 4 years), and
that there is a need for clinical, echocardiographic, or biochemical
parameters to predict delayed recovery, PLVD, or clinical
deterioration.
A number of echocardiographic parameters have been shown to
be associated with a higher likelihood of recovery, including LV
dimensions and systolic function at the time of diagnosis.13 15 Our
findings are consistent with these former studies, showing that echocardiographic markers of advanced remodelling such as enlarged LV
end-diastolic or end-systolic diameter and low LVEF were associated
with increased mortality and non-recovery in our study.
It is unknown when to discontinue heart failure medications in
recovered PPCM patients or whether there is any deterioration
in LV function after an initial recovery in these patients. Amos
et al. reported a lack of deterioration of LV function during an
average follow-up period of 29 months in 15 patients with full recovery who stopped taking medication.10 On the other hand,
Goland et al.16 demonstrated spontaneous deterioration of LV function in three patients, similar to our results. The findings of late deterioration are very important and support the recent report by
Goland et al.16 indicating the need for a close follow-up with
annual determination of cardiac function in women in whom medications are discontinued after complete recovery of LV function.
Recent studies showed that right ventricular systolic function in
PPCM patients is worse than that of patients with idiopathic dilated
899
Deceased (n 510)
P-value
...............................................................................................................................................................................
Age (years)
26.6 + 5.2
28.2 + 5.2
Parity
Follow-up (months)
2.4 + 1.0
44.7 + 8.3
2.9 + 0.9
20.6 + 15.9
0.423
0.113
,0.001
3 (9.4)
2 (20.0)
0.577
Hypertension (n, %)
Diabetes mellitus (n, %)
5 (15.6)
1 (3.1)
2 (20.0)
1 (10.0)
1.000
0.424
8 (25.0)
24 (75.0)
4 (40.0)
6 (60.0)
II
III
6 (18.8)
11 (34.4)
1 (10.0)
2 (20.0)
IV
15 (46.9)
7 (70.0)
0.433
NYHA (n, %)
0.545
Echocardiography
LVESD (cm)
5.6 + 0.6
6.3 + 0.8
0.008
LVEDD (cm)
6.5 + 0.5
7.0 + 0.6
0.053
LVEF (%)
PASP (mmHg)
27.6 + 5.6
43.4 + 11.3
19.7 + 5.6
47.7 + 16.9
,0.001
0.463
2 (6.3)
2 (20.0)
0.236
4.9 + 3.3
649.4 + 316.5
6.3 + 2.7
676.7 + 311.9
0.220
0.481
Digoxin
ACE inhibitor
12 (37.5)
26 (81.3)
3 (30.0)
8 (80.0)
0.428
1.000
Beta-blocker
30 (93.8)
8 (80.0)
0.236
0 (0.0)
2 (20.0)
0.052
CRP (mg/dL)
BNP (pg/mL)
Medication (n, %)
Values are given as the mean + SD or number (percentage) unless otherwise indicated.
ACE, angiotensin-converting enzyme; BNP, brain natriuretic peptide; CRP, C-reactive protein; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection
fraction; LVESD, left ventricular end-systolic diameter; NYHA, New York Heart Association functional class; PASP, pulmonary artery systolic pressure.
Study limitations
Conclusions
In this study we have shown that only 30% of the patients had
normal LV function after 6 months of treatment, but continuing improvement was observed up to the 42th month, and that the recovery phase was not limited to the first 6 months and often
900
M. Biteker et al.
Table 3 Results from patients who recovered and patients who did not recover from peripartum cardiomyopathy
Early recovery (n 5 6)
Non-recovery (n 5 22)
P-value
...............................................................................................................................................................................
Age
25.5 + 6.0
26.6 + 5.3
27.5 + 5.0
0.675
Parity
Follow-up (months)
2.0 + 0.6
41.5 + 3.0
2.8 + 1.2
43.4 + 8.0
2.5 + 0.9
35.4 + 18.7
0.272
0.372
0 (0.0)
1 (7.1)
4 (18.2)
0.532
Hypertension (n, %)
Diabetes mellitus (n, %)
1 (16.7)
0 (0.0)
2 (14.3)
1 (7.1)
4 (18.2)
1 (4.5)
1.000
1.000
2 (33.3)
4 (66.7)
3 (21.4)
11 (78.6)
7 (31.8)
15 (68.2)
II
III
1 (16.7)
3 (50.0)
2 (14.3)
5 (35.7)
4 (18.2)
5 (22.7)
IV
2 (33.3)
7 (50.0)
13 (59.1)
0.896
NYHA (n, %)
0.784
Echocardiography
LVESD (cm)*,
5.2 + 0.3
5.4 + 0.6
6.1 + 0.7
0.001
LVEDD (cm)
6.3 + 0.3
6.5 + 0.5
6.8 + 0.6
0.103
LVEF (%)*,
PASP (mmHg)
30.7 + 3.2
42.5 + 9.2
29.3 + 4.7
45.0 + 9.7
22.1 + 6.1
44.5 + 15.4
0 (0.0)
0 (0.0)
4 (18.2)
0.184
5.0 + 2.9
584.8 + 424.9
5.2 + 4.1
582.7 + 316.9
5.3 + 2.8
660.7 + 319.4
0.983
0.756
Digoxin
ACE inhibitor
1 (16.7)
5 (83.3)
2 (14.3)
12 (85.7)
12 (54.5)
17 (77.3)
0.034
0.862
Beta-blocker
6 (100.0)
13 (92.9)
19 (86.4)
0.641
0 (0.0)
0 (0.0)
2 (9.1)
0.650
CRP (mg/dL)
BNP (pg/mL)
,0.001
0.732
Medication (n, %)
Values are given as the mean + SD or number (percentage) unless otherwise indicated.
ACE, angiotensin-converting enzyme; BNP, brain natriuretic peptide; CRP, C-reactive protein; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection
fraction; LVESD, left ventricular end-systolic diameter; NYHA, New York Heart Association functional class; PASP, pulmonary artery systolic pressure.
*Statistically significant differences between delayed recovery and non-recovery.
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